The Assignment of the Absolute Configuration by NMR using Chiral Derivatizing Agents: A Practical Guide

265 Pages·2015·15.66 MB·English

by  Josi M. Seco

n  T  he Assignment of the Absolute Configuration
by NMR Using Chiral Derivatizing Agents

The Assignment of the
Absolute Configuration
by NMR Using Chiral
Derivatizing Agents
A Practical Guide
José M. Seco,
Emilio Quiñoá
and
Ricardo Riguera
3
3
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Library of Congress Cataloging-in-Publication Data
Seco, J. M. (José Manuel)
The assignment of the absolute configuration by NMR using chiral derivatizing agents : a practical
guide / José M. Seco, Emilio Quiñoá, and Ricardo Riguera.
pages cm
Includes bibliographical references and index.
ISBN 978–0–19–999680–3 (alk. paper) 1. Nuclear magnetic resonance
spectroscopy. 2. Spectrum analysis. 3. Nuclear magnetic resonance spectroscopy—
Problems, exercises, etc. 4. Spectrum analysis—Problems, exercises, etc. I. Quiñoá, E.
(Emilio) II. Riguera, R. (Ricardo) III. Title.
QD96.N8S43 2015
543'.66—dc23
2014042823
9 8 7 6 5 4 3 2 1
Printed in the United States of America
on acid-free paper
n  Contents
Preface  xi
Introduction  xiii
1 The Theoretical Basis for Assignment by NMR  1
1.1. Distinguishing Enantiomers by NMR: The Use of CDAs  1
1.2. Structural Characteristics of the Auxiliaries
and the Substrates  3
1.3. Importance of the Conformation  6
1.4. Importance of the Aromatic Shielding Effect  10
1.5. Use of 13C NMR for Assignment  12
1.6. Simplified Approaches to Assignment by NMR  13
1.6.1. Single-Derivatization Method: Manipulating the
Conformational Equilibrium by Temperature  13
1.6.2. Single-Derivatization Method: Manipulating the
Conformational Equilibrium by Complexation  14
1.6.3. Single-Derivatization Method Based on
Esterification Shifts  16
1.6.4. Mix-and-Shake Method: Assignment Using
Resin-Bound CDAs  18
1.7. General Criteria for the Correct Application of the NMR
Methodology  18
1.8. Correlation Models for the Assignment of Polyfunctional
Compounds  21
1.9. Summary  22
2 Practical Aspects of the Preparation of the Derivatives  27
2.1. Instrumentation, Concentration, Solvent, and
Temperature of the NMR Experiment  27
2.2. Source and Preparation of the CDAs  27
2.3. Preparation of the CDA Esters, Thioesters, and Amides  28
2.3.1. Derivatization of Alcohols, Thiols, and Cyanohydrins
Using the CDA Acid  28
2.3.2. Derivatization of Amines Using the CDA Acid  28
2.3.3. Preparation of the CDA Acid Chlorides  29
2.3.4. Derivatization of Alcohols, Thiols, and Cyanohydrins
Using the CDA Acid Chloride  29
2.4. Resin-Bound CDA Derivatives (Mix-and-Shake Method)  29
2.4.1. Preparation of Resin-Bound CDA Derivatives  30
2.4.2. Preparation of Acid Chloride Resins  30
v
vi n Contents
2.4.3. Preparation of CDA-Resins  31
2.4.4. Determination of the Loading of the CDA-Resins  31
2.4.5. In-Tube Derivatization of Amines  31
2.4.6. In-Tube Derivatization of Primary and Secondary
Alcohols, Cyanohydrins, and Secondary Thiols  32
2.4.7. In-Tube Derivatization of Amino Alcohols  34
2.4.8. In-Tube Derivatization of Diols and Triols  35
2.4.9. In-Tube Derivatization for Single-Derivatization Procedures  35
3 Assignment of the Absolute Configuration of Monofunctional
Compounds by Double Derivatization  37
3.1. Secondary Alcohols  37
3.1.1. MPA and 9-AMA as CDAs for Secondary Alcohols  37
3.1.2. Example 1: Assignment of the Absolute Configuration
of Diacetone D-Glucose Using MPA  39
3.1.3. Example 2: Assignment of the Absolute Configuration
of (−)-Isopulegol Using 9-AMA  40
3.1.4. Example 3: Assignment of the Absolute Configuration
of (R)-Butan-2-ol Using MPA and 13C-NMR  42
3.1.5. Simultaneous Derivatization of the Substrate with the
(R)- and (S)-CDAs  43
3.1.6. Example 4: Assignment of the Absolute Configuration
of (S)-Butan-2-ol Using a 1:2 Mixture of (R)- and (S)-MPA  44
3.1.7. Example 5: Assignment of the Absolute Configuration
of (−)-Menthol Using a 2:1 Mixture of (R)- and
(S)-9-AMA and 13C NMR  45
3.1.8. MTPA as the CDA for Secondary Alcohols  47
3.1.9. Example 6: Assignment of the Absolute Configuration
of (−)-Borneol Using MTPA  47
3.1.10. Summary  48
3.2. β-Chiral Primary Alcohols  51
3.2.1. Assignment of β-Chiral Primary Alcohols as 9-AMA Esters  51
3.2.2. Example 7: Assignment of the Absolute Configuration
of (S)-2-Methylbutan-1-ol Using 9-AMA  52
3.2.3. Absolute Configuration of Primary Alcohols with Polar
Groups as 9-AMA Esters  53
3.2.4. Example 8: Assignment of the Absolute Configuration
of (S)-2-Chloropropan-1-ol Using 9-AMA  55
3.2.5. Summary  56
3.3. Aldehyde Cyanohydrins  58
3.3.1. Assignment of Aldehyde Cyanohydrins as MPA Esters  58
3.3.2. Example 9: Assignment of the Absolute Configuration
of (R)-2-Hydroxy-3-Methylbutanenitrile Using MPA  59
3.3.3. Example 10: Assignment of the Absolute Configuration
of (R)-2-Hydroxy-2-(4-Methoxyphenyl)Acetonitrile
Using MPA and 13C NMR  60
Contents n vii
3.3.4. Summary  63
3.4. Ketone Cyanohydrins  63
3.4.1. Assignment of Ketone Cyanohydrins as MPA Esters  65
3.4.2. Example 11: Assignment of the Absolute Configuration
of (1R, 2S, 5R)-1-Hydroxy-2-Isopropyl-5-
Methylcyclohexanecarbonitrile Using MPA  65
3.4.3. Example 12: Assignment of the Absolute Configuration
of (S)-2-Hydroxy-2,4-Dimethylpentanenitrile Using
MPA and 13C NMR  67
3.4.4. Summary  69
3.5. Secondary Thiols  69
3.5.1. MPA and 2-NTBA Thioesters of Secondary Thiols  69
3.5.2. Example 13: Assignment of the Absolute Configuration
of (S)-Butane-2-Thiol Using MPA  71
3.5.3. Example 14: Assignment of the Absolute Configuration
of (R)-Ethyl 2-Mercaptopropanoate Using 2-NTBA  72
3.5.4. Example 15: Assignment of the Absolute Configuration
of (R)-Ethyl 2-Mercaptopropanoate Using 2-NTBA and
13C NMR  73
3.5.5. Summary  76
3.6. α-Chiral Primary Amines  76
3.6.1. BPG as the CDA for α-Chiral Primary Amines  76
3.6.2. Example 16: Assignment of the Absolute Configuration
of (−)-Isopinocampheylamine Using BPG  78
3.6.3. Example 17: Assignment of the Absolute Configuration
of (S)-Butan-2-Amine Using BPG and 13C NMR  79
3.6.4. MPA as the CDA for α-Chiral Primary Amines  80
3.6.5. Example 18: Assignment of the Absolute Configuration
of (−)-Bornylamine Using MPA  82
3.6.6. MTPA as the CDA for α-Chiral Primary Amines  83
3.6.7. Example 19: Assignment of the Absolute Configuration
of (−)-Bornylamine Using MTPA  83
3.6.8. Summary  84
3.7. α-Chiral Carboxylic Acids  87
3.7.1. 9-AHA Esters of Carboxylic Acids  89
3.7.2. Example 20: Assignment of the Absolute Configuration
of (S)-3-(Acetylthio)-2-Methylpropanoic Acid Using 9-AHA  90
3.7.3. Summary  91
4 Assignment of the Absolute Configuration of Monofunctional
Compounds by Single Derivatization  93
4.1. Low-Temperature NMR Procedure for Secondary Alcohols  93
4.1.1. Example 21: Assignment of the Absolute Configuration
of Diacetone D-Glucose Using (R)-MPA  95
4.1.2. Example 22: Assignment of the Absolute Configuration
of (R)-Butan-2-ol Using (S)-MPA  98
viii n Contents
4.2. Complexation with Ba2+: MPA Esters of Secondary Alcohols  99
4.2.1. Example 23: Assignment of the Absolute Configuration
of (R)-Pentan-2-ol Using (S)-MPA  100
4.2.2. Example 24: Assignment of the Absolute Configuration
of (R)-Pentan-2-ol Using (R)-MPA  101
4.3. Complexation with Ba2+: MPA Amides of α-Chiral
Primary Amines  102
4.3.1. Example 25: Assignment of the Absolute Configuration
of (−)-Isopinocampheylamine Using (R)-MPA  105
4.4. Esterification Shifts  105
4.4.1. Example 26: Assignment of the Absolute Configuration
of (1R, 4S)-Hydroxycyclopent-2-en-1-yl Acetate as
(R)-9-AMA Ester  107
4.4.2. Example 27: Assignment of the Absolute Configuration
of (1R, 4S)-Hydroxycyclopent-2-en-1-yl Acetate as
(S)-9-AMA Ester  108
4.5. Summary  109
5 Assignment of the Absolute Configuration of Polyfunctional
Compounds  111
5.1. Sec/Sec-1,2- and Sec/Sec-1,n-Diols  111
5.1.1. Double-Derivatization Methods: MPA, 9-AMA, and MTPA  111
5.1.2. Example 28: Assignment of the Absolute Configuration
of Heptane-2,3-Diol (Syn)  116
5.1.3. Example 29: Assignment of the Absolute Configuration
of Heptane-2,3-Diol (Anti)  118
5.1.4. Example 30: Assignment of the Absolute Configuration
of 1,4-Bis-O-(4-Chlorobenzyloxy)-D-Threitol (Syn)
Using 13C NMR  119
5.1.5. Single-Derivatization Methods: MPA  120
5.1.6. Example 31: Assignment of the Absolute Configuration
of a Pure Isomer of 3,4-Dihydroxy-5-Methylhexan-2-One  124
5.1.7. Example 32: Assignment of the Absolute Configuration
of Another Isomer of 3,4-Dihydroxy-5-Methylhexan-2-One  124
5.1.8. Summary  125
5.2. Sec/Sec-1,2-Amino Alcohols  127
5.2.1. Double-Derivatization Method: MPA  127
5.2.2. Example 33: Assignment of the Absolute Configuration
of 2-Aminopentan-3-ol (Syn)  130
5.2.3. Example 34: Assignment of the Absolute Configuration
of Methyl 4-Amino-3-Hydroxy-5-Phenylpentanoate (Anti)  132
5.2.4. Summary  133
5.3. Prim/Sec-1,2-Diols  134
5.3.1. Double-Derivatization Methods: MPA  135
Contents n ix
5.3.2. Example 35: Assignment of the Absolute Configuration
of (S)-Propane-1,2-Diol Using MPA  138
5.3.3. Double-Derivatization Methods: 9-AMA  140
5.3.4. Example 36: Assignment of the Absolute Configuration
of (S)-Propane-1,2-Diol Using 9-AMA  143
5.3.5. Example 37: Assignment of the Absolute Configuration
of (R)-2,3-Dihydroxypropyl Stearate Based Only on the
Methylene Hydrogens  144
5.3.6. Example 38: Assignment of the Absolute Configuration
of (R)-1-Phenylethane-1,2-Diol Based Only on the
Methylene Hydrogens  145
5.3.7. Single-Derivatization Method: MPA  147
5.3.8. Example 39: Assignment of the Absolute Configuration
of (S)-Propane-1,2-Diol  150
5.3.9. Example 40: Assignment of the Absolute Configuration
of (R)-Propane-1,2-Diol  152
5.3.10. Summary  154
5.4. Sec/Prim-1,2-Amino Alcohols  155
5.4.1. Double-Derivatization Methods: MPA and the Use of R
and Methylene Hydrogens 155
5.4.2. Example 41: Assignment of the Absolute Configuration
of (S)-2-Aminopropan-1-ol Based on R and Methylene
Hydrogens 157
5.4.3. Double-Derivatization Methods: The Use of OMe and
CαH Signals for Assignment  157
5.4.4. Example 42: Assignment of the Absolute Configuration
of (S)-2-Aminopropan-1-ol Using ΔδRS of OMe and
CαH signals  159
5.4.5. Example 43: Assignment of the Absolute Configuration
of (S)-2-Aminopropan-1-ol Using the Separation of
OMe and CαH Signals  161
5.4.6. Example 44: Assignment of the Absolute Configuration
of (R)-2-Amino-3-Methylbutan-1-ol Using the
Separation of OMe and CαH Signals  163
5.4.7. Single-Derivatization Method: MPA  165
5.4.8. Example 45: Assignment of the Absolute Configuration
of (S)-2-Aminopropan-1-ol by Low-Temperature NMR
of a Single Derivative  167
5.4.9. Example 46: Assignment of the Absolute Configuration
of (R)-2-Aminopropan-1-ol by Low-Temperature NMR
of a Single Derivative  168
5.4.10. Summary  171
5.5. Prim/Sec-1,2-Amino Alcohols  172
5.5.1. Double-Derivatization Methods: MPA and the Use of R
and Methylene Hydrogens  173